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Expression of cytochromes P450 (CYP) is markedly reduced during inflammatory processes. In vitro studies with hepatocytes have shown that cytokines generated during these processes down-regulate CYP. However, it is not clear to what extent each individual cytokine contributes to the overall reduced expression of the various CYP isoenzymes in vivo. Interleukin 6 (IL-6), a major player during inflammatory processes, is recognized as the most important cytokine modulating the hepatic expression of acute-phase protein (APP) genes. For this reason, we selected the IL-6 ؊/؊ mouse as a model to investigate the role of IL-6 in the down-regulation of hepatic CYP during experimental inflammation. Our results show that the reduction in messenger RNA (mRNA) levels of CYP1A2, CYP2A5, and CYP3A11 during turpentine-induced inflammation was abrogated in IL-6-deficient mice, confirming that IL-6 is an indispensable player for the down-regulation of hepatic CYP during aseptic inflammation. Moreover, the different CYP isoenzymes showed a variable grade of dependence on IL-6, CYP2A5 being the most sensitive one. In the case of CYP2E1, differences between IL-6 ؊/؊ and wild-type mice were no longer maintained after 24 hours, suggesting a delayed, rather than abrogated, CYP downregulation in the absence of IL-6. As opposed to that, hepatic CYP repression took place in IL-6-deficient mice during lipopolysaccharide (LPS)-mediated inflammation. This contrasting behavior observed for CYP is surprisingly similar to the one seen for extracellular (serum amyloid A, ␤-fibrinogen) and intracellular (metallothionein-1) APPs and points to the fact that, in the model of bacterial inflammation (LPS), the effects of IL-6 on CYP downregulation are likely to be substituted by other cytokines or mediators. (HEPATOLOGY 2000;32:49-55.)

Interleukin (IL)-6 and IL-6-type cytokines signal through the gp130/Jak/STAT signal transduction pathway. The key components involved are the signal transducing receptor subunit gp130, the Janus kinases Jak1, Jak2 and Tyk2, STAT1 and STAT3 of the family of signal transducers and activators of transcription, the protein tyrosine phosphatase SHP2 and the suppressors of cytokine signalling SOCS1, SOCS2 and SOCS3. Whereas considerable information has been accumulated concerning the time-course of activation for the individual signalling molecules, data on the availability of the proteins involved in IL-6-type cytokine signal transduction are scarce. Nevertheless, availability of these molecules, determined by the balance of protein synthesis and degradation, also influences IL-6-type cytokine signal transduction. Here, we present a comprehensive set of data on the halflives of the key molecules involved in the IL-6 signal transduction pathway. The turnover rates for the various proteins differ substantially. Three groups of signalling proteins can be discriminated: whereas the feedback inhibitors SOCS1, SOCS2 and SOCS3 are very short-lived, STAT1, STAT3 and SHP2 have an extremely slow turnover rate. Interestingly, the half-life of STAT3b, a splice variant of STAT3a, is reduced to almost 50% of the half-life of STAT3a. The Janus kinases Jak1, Jak2, Tyk2 and gp130 show intermediate half-lives. Our data imply that signalling components activated by post-translational modifications are long-lived whereas the activity of very short-lived proteins is regulated mainly at the transcriptional level.Keywords: half-life; interleukin-6; interleukin-6-type cytokines; protein turnover; signal transduction.Interleukin-6 (IL-6) is a multifunctional cytokine which is involved in the regulation of complex cellular processes including proliferation, differentiation and gene activation. Among others, it plays a crucial role during haematopoesis and liver-specific processes such as acute-phase protein synthesis and liver regeneration. IL-6 and IL-6-type cytokines signal through the glycoprotein (gp)130/Jak/STAT pathway [1]: IL-6 exerts its action via a surface receptor complex composed of the specific interleukin-6 receptor a-chain (IL-6R; gp80) and the common signal transducer gp130. Binding of IL-6 to its receptor induces dimerization of gp130 [2,3], activation of the gp130-associated protein tyrosine kinases of the Janus kinase family Jak1, Jak2 and Tyk2 and phosphorylation of gp130 at cytoplasmic tyrosine residues [4,5]. These phosphotyrosines serve as docking sites for SH2-domain containing proteins such as the signal transducers and activators of transcription (STATs) STAT1 [6], STAT3 [6,7] and the protein tyrosine phosphatase SHP2 [7] which themselves become subsequently tyrosine phosphorylated. Jak1 was found to be essential for gp130-, , and SHP2-phosphorylation [9]. The phosphorylated STAT factors form homo-or heterodimers, translocate into the nucleus and bind to enhancers of IL-6 inducible genes [10,11]. SHP2 is believed to ...

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